A team of scientists from Instituto Sloan Kettering (United States) has identified the STING cell signaling pathway as a key piece for prevent latent cancer cells from progressing into aggressive tumors months, or even years, after having escaped from a primary tumor. The findings, published in the ‘Nature’ magazine‘, suggest that drugs that activate STING could help prevent the spread of cancer to new places in the body, a process known as metastasis.
In mouse models of lung cancer, treatment that stimulated the STING pathway helped kill lingering cancer cells and prevent them from progressing to aggressive metastases. Known as micrometastases, these cells, which can be found singly or in small groups, are too small to be detected with standard imaging tests. “Most cancer deaths are due to metastasis,” says the Dr. John Massague, The study’s lead author and director of the Sloan Kettering Institute, a center for basic science and translational research at Memorial Sloan Kettering Cancer Center (MSK).
Dr. Massagué: “This research identified a hitherto unknown role of STING signaling in suppressing the development of aggressive metastases”
“Anything we can do to prevent these cells from waking up again or to help the immune system kill them could be of great benefit to many people,” Add. “This investigation identified a hitherto unknown role of STING signaling in the suppression of the development of aggressive metastases”. Even when a primary tumor is successfully treated, cells that have broken away from the tumor often remain in the body in a dormant state that allows them to evade detection by the immune system for years. Then, once the dormant cells have developed new features that help them survive, they can wake up and start their uncontrolled growth again.
SHORTCUT FROM THE START
Instead of focusing on the advanced stages of the disease, when large and aggressive metastases have already appeared, the researchers focused on the initial phases, that is, after the cancer has developed but before it has been able to successfully establish itself in new parts of the body, explains Dr. Jing Hu, principal investigator of the Massagué laboratory and first author of the study. “For example, almost half of the patients diagnosed with stage 1 or 2 lung adenocarcinoma will develop metastases,” Explain. “At the time of diagnosis, we believe that in many of these patients some cancer cells will have already detached from their primary tumor and have moved to other organs, where they will remain in a latent state until they wake up and generate what we call spontaneous or breakthrough metastases. “.
Many of these cancer cells that break away from a primary tumor will die during their journey through the bloodstream to distant organs, but those that survive learn to adapt to aggression and stresss of the human body. “Initially, tumor cells are not in a favorable environment and have to adapt and develop their own niche of self-sufficiency until they are ready,” Hu explains. “Then they start a rapidly growing metastasis. The interaction with the person’s immune system is very important for this process.”
Using mouse models of early-stage metastasis of lung cancer, the research team performed a genetic screen to look at the activity of tumor cell genes that are important for interactions with the host’s immune system. Thus they identified the STING pathway -acronym for stimulator of interferon genes- as a suppressor of metastatic sprouts. “This makes a lot of sense to us because STING signaling is known to be important in triggering a immune response against cells diseased by viruses or cancer mutations,” adds Hu.
The researchers found that STING expression changes at different stages of metastasis. In the latent phase, STING activity is low, and dormant cells are excellent at hiding from immune defenses. Upon exiting the latent phase and entering the proliferative phase, metastatic cells begin to have increased STING activity. This makes them more vulnerable to attacks by the immune system. But cells that survive this bottleneck to generate larger clumps, called macrometastases, again show reduced levels of STING, making them more resistant to the immune system.
Dr. Massagué: “The use of STING activators together with this window of increased STING activity in revived cancer cells could be an opportunity to help the body’s immune defenses to destroy them”
“This means that these tumor cells will be recognized differently by the immune system in the different phases of metastasis development”, explains Dr. Massagué. “The use of STING activators together with this window of increased STING activity in revived cancer cells could be an opportunity to help the body’s immune defenses to destroy them.”
In fact, when the scientists artificially increased STING signaling in those aggressive metastatic cells, they attracted to more immune advocates like natural killer cells and T cells, which pounced on them to finish them off. And when the scientists activated STING in mice lacking key immune cells, the metastases continued to develop, pointing to a critical role for STING in recruiting immune cells to attack cancer cells.
However, these tiny micrometastases are much easier to study in mice than in people. So, to test the applicability of their findings, the scientists compared their observations in mouse models with small amounts of cancer cells found in the lymph nodes of cancer patients of the lung in the initial phase. What they observed in the patients corroborated what they had discovered in the laboratory. The team also identified a new role for the signaling molecule TGF-beta in suppressing STING activity during the latent phase of metastasis.
Drugs that increase STING activity, known as STING agonists, are already being tested in some clinical trials.
Drugs that increase STING activity, known as STING agonists, are already being tested in some clinical trials, Hu notes, but those trials are for patients with advanced cancers, where aggressive metastases have already developed. By then, the tumor cells have already remodeled their local environment to better protect themselves from attacks by the host’s immune system. “In the early stages of metastasis, STING agonists may have a better effect”, notes Dr. Hu. “At that point, the tumor has not yet fully established a microenvironment for itself that evades the immune system, and STING signaling within tumor cells will be enhanced.”
Ultimately, the researchers hope to collaborate with clinicians to develop a clinical trial addressing the newly discovered vulnerabilities of micrometastases in patients with early-stage disease. One possibility would be to take advantage of STING to kill cells before they can start to metastasize. Another possibility would be to try to keep cells dormant forever. In the meantime, the Massagué laboratory continues to explore the ability of STING agonists to kill persistent metastatic cells, as well as the potential opportunities to take advantage of TGF-beta against early-stage metastasis.
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